1. Field of the Invention
The present invention is directed to digoxin and more particularly, a novel and unique solid dosage form for orally administering digoxin to warm-blooded animals, e.g., humans.
2. Description of the Prior Art
Digoxin is a cardiotonic drug, used in the field of medicine to achieve an increase in the force of myocardial contraction. Essentially, digoxin is a conduction system depressant which acts in such a manner as to decrease cardiac rate.
The structural formula for digoxin is set out below, and conventionally speaking, the dose administered to a patient (orally) to achieve digitalization is approximately 1.5 mg initially, and thereafter, a maintenance dose of approximately 0.5 mg is usually required. ##STR1##
Digoxin is used in the treatment of cardiac failure, atrial fibrillation and flutter, paroxysinal tachycardia, cardiac insufficiency, etc. This compound has the advantage as compared to digitoxin, and that its onset of action is quite more rapid, and further, its duration of action is relatively shorter. This compound has an additional advantage in that in the event of an overdose, the symptoms associated therewith are more readily dissipated.
Recently, many articles have been published on the variation in the absorption of digoxin, administered via conventional oral solid dosage forms, e.g., tablets, capsules, etc. These variations in digoxin absorption have been noted in both inter- and intrapatient studies. While potential sources of digoxin variability from standard oral solid dosage form formulations and/or oral administration have been postulated and investigated, no real answer to the problem has been determined.
The digoxin molecule consists of a steroidal (digoxigenin) nucleus in glycosidic linkage with three sugar(digitoxose) moieties. The present inventors have determined that each of these sugar moieties are prone to acid "cleavage" or hydrolysis under acidic conditions (synonymous with the acidic environment of the stomach, pH=1). Accordingly, the present inventors have further determined that conventional oral solid dosage formulations intended to deliver digoxin are inappropriate in that the drug in such formulations is subject to hydrolytic attack in the acid environment of the stomach, the result of which is a sequential cleavage of the three sugar moieties on the overall steroidal digoxin nucleus. As a consequence thereof, the delivery of therapeutic and undegraded levels of digoxin is greatly impeded.
In the past, numerous attempts at improving the solubility of digoxin via molecular modification have been made. See, U.S. Pat. No. 3,884,905. However, the present inventors believe their discovery is the first discovery specifically dealing with the inability of digoxin to be absorbed as the intact (undegraded) molecule. Very recently, it has been proposed to deliver digoxin via "soft" gelatin capsules. While such approach might aid in the basic delivery of digoxin, such approach does not solve the degradation phenomenon discussed earlier due to the fact that the drug in soft gelatin capsules is subject to attack in the acidic environment of the stomach.